Pathology in the control of cell-cycle kinetics has been shown to be important in carcinogenesis. It has been proposed that the development of malignant tumors may result from a basic defect in the ability of cancer cells to control their growth rate during the G1 phase of the cell cycle. Cancer is, however, not only a disease of accelerated uncontrolled growth. Cancer is also characterized by aberrant control of cellular differentiation. My laboratory has recently obtained new data which suggests that there may be a common mechanism which couples the control of cell growth and cell differentiation. We have found that there is a specific arrest point in the G1 phase of the cell cycle associated with control of cell differentiation. We have designated this arrest point GD and have shown it to be distinct from the G1 serum arrest point and from the G1-nutrient arrest point. GD is the only G1 arrest point at which cell differentiation occurs. GD arrested cells are also unique in their insensitivity to growth restimulation by serum, growth factors, and nutrients. Based on these observations we propose that the coupling of control of cell proliferation and differentiation in normal cells is mediated by metabolic events that occur at the GD arrest point. We also propose that carcinogenesis results from a defect in the coupling of growth and differentiation at GD. The studies detailed in this proposal attempt to identify the specific biochemical events that couple control of growth and differentiation and to show that such coupling is defective in neoplastic cells. We also propose to identify new pharmacological or biochemical agents that can modulate this coupling mechanism and that promote tumor cell differentiation and to inhibit tumor cell growth.